Homologation of Isocyanates with Lithium Carbenoids: A Straightforward Access to α-Halomethyl- and α,α-Dihalomethylamides

Abstract

Treatment of widely available isocyanates with monohalolithium and dihalolithium carbenoids provides a valuable protocol for the one-pot preparation of α-halo- and α,α-dihaloacetamide derivatives. While monohalolithium carbenoids can be prepared by a smooth lithium–halogen exchange, the preparation of the corresponding dihalo compounds proved to be highly dependent on the base used to realize the deprotonation, with lithium 2,2,6,6-tetramethylpiperidine emerging as optimal. The clear advantages of the procedure are: (a) broad scope of isocyanates that can be employed; (b) preservation of the optical purity when chiral materials are used; (c) divergent access to different haloamides by simply selecting the homologating agents. We also report an application of Charette’s imidoyl triflate activation of a secondary amide to the synthesis of an α-chloro ketone and ¹⁵N NMR data for selected compounds.

Key words

amides - carbenoids - lithiation - halides - nucleophilic addition

• References

• 1 Contributed equally to the work.
• 2 Concellón JM, Bardales E. Eur. J. Org. Chem. 2004; 1523
• 3a Gunnlaugsson T, MacDónaill DA, Parker D. J. Am. Chem. Soc. 2001; 123: 12866
• 3b Harte AJ, Gunnlaugsson T. Tetrahedron Lett. 2006; 47: 6321
• 4a Fujii I, Tanaka F, Miyashita H, Tanimura R, Kinoshita K. J. Am. Chem. Soc. 1995; 117: 6199
• 4b Renslo AR, Jaishankar P, Venkatachalam R, Hackbarth C, Lopez S, Patel DV, Gordeev MF. J. Med. Chem. 2005; 48: 5009
• 5a Davies DT, Kapur N, Parsons AF. Tetrahedron Lett. 1999; 40: 8615
• 5b Ishibashi H, Haruki S, Uchiyama M, Tamura O, Matsuo J.-i. Tetrahedron Lett. 2006; 47: 6263
• 6a Voloshchuk N, Lee MX, Zhu WW, Tanrikulu IC, Montclare JK. Bioorg. Med. Chem. Lett. 2007; 17: 5907
• 6b Wang Z, Li F, Zhao L, He Q, Chen F, Zheng C. Tetrahedron 2011; 67: 9199
• 7 Yang Y, Shang P, Cheng C, Wang D, Yang P, Zhang F, Li T, Lu A, Zhao Y. Eur. J. Med. Chem. 2010; 45: 4300
• 8a Paczal A, Bényei AC, Kotschy A. J. Org. Chem. 2006; 71: 5969
• 8b Morimoto H, Fujiwara R, Shimizu Y, Morisaki K, Ohshima T. Org. Lett. 2014; 16: 2018
• 8c Hodgson DM, Labande AH, Muthusamy S. Org. React. 2013; 80: 133-496
• 9a Jung J.-W, Shin D.-Y, Seo S.-Y, Kim S.-H, Paek S.-M, Jung J.-K, Suh Y.-G. Tetrahedron Lett. 2005; 46: 573
• 9b Pace V, Castoldi L, Holzer W. J. Org. Chem. 2013; 78: 7764
• 9c Murai T, Mutoh Y. Chem. Lett. 2012; 41: 2
• 10a Liu W, Hua J, Zhou J, Zhang H, Zhu H, Cheng Y, Gust R. Bioorg. Med. Chem. Lett. 2012; 22: 5008
• 10b Ma L, Chen J, Liang X, Xie C, Deng C, Huang L, Peng A, Wei Y, Chen L. Arch. Pharm. (Weinheim, Ger.) 2012; 345: 517
• 11 Stephen A, Schulz G, Reinshagen H. Justus Liebigs Ann. Chem. 1974; 363
• 12 Liu W.-B, Chen C, Zhang Q, Zhu Z.-B. Beilstein J. Org. Chem. 2012; 8: 344
• 13 Wang J, Li H, Zhang D, Huang P, Wang Z, Zhang R, Liang Y, Dong D. Eur. J. Org. Chem. 2013; 5376
• 14a Braun M In The Chemistry of Organolithium Compounds . Rappoport Z, Marek I. John Wiley and Sons; Chichester: 2004
• 14b Siegel H. Lithium Halocarbenoids – Carbanions of High Synthetic Versatility. In Topics in Current Chemistry. Vol. 106. Springer; Berlin: 1982: 55
• 14c Capriati V, Florio S. Chem. Eur. J. 2010; 16: 4152
• 14d Pace V. Aust. J. Chem. 2014; 67: 311
• 15 Köbrich G, Akhtar A, Ansari F, Breckoff WE, Büttner H, Drischel W, Fischer RH, Flory K, Fröhlich H, Goyert W, Heinemann H, Hornke I, Merkle HR, Trapp H, Zündorf W. Angew. Chem., Int. Ed. Engl. 1967; 6: 41
• 16a Tarhouni R, Kirschleger B, Rambaud M, Villieras J. Tetrahedron Lett. 1984; 25: 835
• 16b Sadhu KM, Matteson DS. Tetrahedron Lett. 1986; 27: 795
• 16c Michnick TJ, Matteson DS. Synlett 1991; 631
• 16d Kapeller DC, Hammerschmidt F. J. Am. Chem. Soc. 2008; 130: 2329
• 17a Concellón JM, Cuervo H, Fernández-Fano R. Tetrahedron 2001; 57: 8983
• 17b Pace V, Castoldi L, Holzer W. Adv. Synth. Catal. 2014; 356: 1761
• 17c Barluenga J, Llavona L, Bernad PL, Concellón JM. Tetrahedron Lett. 1993; 34: 3173
• 17d Barluenga J, Baragaña B, Concellón JM. J. Org. Chem. 1999; 64: 2843
• 18a Concellón JM, Rodríguez-Solla H, Simal C. Org. Lett. 2008; 10: 4457
• 18b Concellón JM, Rodríguez-Solla H, Bernad PL, Simal C. J. Org. Chem. 2009; 74: 2452
• 18c Bull JA, Boultwood T, Taylor TA. Chem. Commun. 2012; 48: 12246
• 18d Boultwood T, Affron DP, Trowbridge AD, Bull JA. J. Org. Chem. 2013; 78: 6632
• 19 Barluenga J, Fernandez-Simon JL, Concellón JM, Yus M. J. Chem. Soc., Perkin Trans. 1 1989; 77
• 20a Barluenga J, Baragaña B, Alonso A, Concellón JM. J. Chem. Soc., Chem. Commun. 1994; 969
• 20b Barluenga J, Baragaña B, Concellón JM. J. Org. Chem. 1995; 60: 6696
• 20c Barluenga J, Baragaña B, Concellón JM, Piñera-Nicolás A, Díaz MR, García-Granda S. J. Org. Chem. 1999; 64: 5048
• 20d Kowalski CJ, Reddy RE. J. Org. Chem. 1992; 57: 7194
• 21 Pace V, Holzer W, Verniest G, Alcántara AR, De Kimpe N. Adv. Synth. Catal. 2013; 355: 919
• 22 Boche G, Lohrenz JC. W. Chem. Rev. 2001; 101: 697
• 23 Schäfer G, Matthey C, Bode JW. Angew. Chem. Int. Ed. 2012; 51: 9173
• 24a Sleebs BE, Hughes AB. J. Org. Chem. 2007; 72: 3340
• 24b Kimmerlin T, Seebach D. Helv. Chim. Acta 2003; 86: 2098
• 25a Zhang Y, Wang J. Chem. Commun. 2009; 0: 5350
• 25b Podlech J In Enantioselective Synthesis of β-Amino Acids . Juaristi E, Soloshonok VA. John Wiley & Sons; New York: 2005
• 25c Bernardim B, Pinho VD, Burtoloso AC. B. J. Org. Chem. 2012; 77: 9926
• 26 Hughes AB, Sleebs BE. Synth. Commun. 2008; 39: 48
• 27 Cahiez G, Normant JF. Tetrahedron Lett. 1977; 18: 3383
• 28a Saraireh IA. M. Tetrahedron Lett. 2012; 53: 2023
• 28b Hughes AB, Sleebs BE. Aust. J. Chem. 2008; 61: 131
• 29 Plucińska K, Liberek B. Tetrahedron 1987; 43: 3509
• 30 Pace V, Castoldi L, Holzer W. Chem. Commun. 2013; 49: 8383
• 31a Nahm S, Weinreb SM. Tetrahedron Lett. 1981; 22: 3815
• 31b Balasubramaniam S, Aidhen IS. Synthesis 2008; 3707
• 31c Pace V, Castoldi L, Alcantara AR, Holzer W. RSC Adv. 2013; 3: 10158
• 32a Pace V. Aust. J. Chem. 2012; 65: 301
• 32b Pace V, Hoyos P, Castoldi L, Domínguez de María P, Alcántara AR. ChemSusChem 2012; 5: 1369
• 32c Pace V, Hoyos P, Fernández M, Sinisterra JV, Alcántara AR. Green Chem. 2010; 12: 1380
• 32d Pace V, Alcántara AR, Holzer W. Green Chem. 2011; 13: 1986
• 32e Pace V, Castoldi L, Hoyos P, Sinisterra JV, Pregnolato M, Sánchez-Montero JM. Tetrahedron 2011; 67: 2670
• 32f Pace V, Castoldi L, Alcántara AR, Holzer W. Green Chem. 2012; 14: 1859
• 32g Pace V. Curr. Org. Chem. 2013; 17: 1131
• 32h Pace V, Castoldi L, Hernáiz MJ, Alcántara AR, Holzer W. Tetrahedron Lett. 2013; 54: 4369
• 32i Pace V, Hoyos P, Alcántara AR, Holzer W. ChemSusChem 2013; 6: 905
• 32j Pace V, Rae JP, Procter DJ. Org. Lett. 2014; 16: 476
• 33a Charette AB, Beauchemin A. Org. React. 2004; 58: 1-415
• 33b Ke Z, Zhou Y, Gao H, Zhao C, Phillips DL. Chem. Eur. J. 2007; 13: 6724
• 34 Ellmerer-Müller EP, Brössner D, Maslouh N, Takó A. Helv. Chim. Acta 1998; 81: 59
• 35a Barluenga J, Llavona L, Yus M, Concellón JM. Tetrahedron 1991; 47: 7875
• 35b Barluenga J, Llavona L, Concellón JM, Yus M. J. Chem. Soc., Perkin Trans. 1 1991; 297
• 35c Taguchi H, Yamamoto H, Nozaki H. Bull. Chem. Soc. Jpn. 1977; 50: 1588
• 35d Taguchi H, Yamamoto H, Nozaki H. J. Am. Chem. Soc. 1974; 96: 6510
• 36 Liu XD, Kimura M, Sudo A, Endo T. J. Polym. Sci., Part A: Polym. Chem. 2010; 48: 5298
• 37 Onishi T, Otake Y, Hirose N, Nakano T, Torii T, Nakazawa M, Izawa K. Tetrahedron Lett. 2001; 42: 6337
• 38a Pace V, Martínez F, Fernández M, Sinisterra JV, Alcántara AR. Adv. Synth. Catal. 2009; 351: 3199
• 38b Pace V, Verniest G, Sinisterra JV, Alcántara AR, De Kimpe N. J. Org. Chem. 2010; 75: 5760
• 38c Pace V, Holzer W. Tetrahedron Lett. 2012; 53: 5106
• 39 Bechara WS, Pelletier G, Charette AB. Nat. Chem. 2012; 4: 228
• 40a Charette AB, Grenon M, Lemire A, Pourashraf M, Martel J. J. Am. Chem. Soc. 2001; 123: 11829
• 40b Barbe G, Charette AB. J. Am. Chem. Soc. 2008; 130: 18
• 40c Xiao K.-J, Luo J.-M, Ye K.-Y, Wang Y, Huang P.-Q. Angew. Chem. Int. Ed. 2010; 49: 3037
• 40d Xiao K.-J, Wang A.-E, Huang P.-Q. Angew. Chem. Int. Ed. 2012; 51: 8314
• 40e Xiao K.-J, Luo J.-M, Xia X.-E, Wang Y, Huang P.-Q. Chem. Eur. J. 2013; 19: 13075
• 40f Xiao K.-J, Wang A.-E, Huang Y.-H, Huang P.-Q. Asian J. Org. Chem. 2012; 1: 130
• 40g Pace V, Holzer W. Aust. J. Chem. 2013; 66: 507
• 41 Arjunan V, Mohan S, Subramanian S, Thimme Gowda B. Spectrochim. Acta, Part A 2004; 60: 1141
• 42 Fuchter MJ, Smith CJ, Tsang MW. S, Boyer A, Saubern S, Ryan JH, Holmes AB. Chem. Commun. 2008; 2152
• 43 Braun JV, Jostes F, Münch W. Justus Liebigs Ann. Chem. 1927; 453: 113